B cells regulate thymic CD8+T cell differentiation in lupus-prone mice.

Chen Xing,Gencheng Han,Beifen Shen,Xiaoling Liu,Guojiang Chen,Yan Li,Ning Ma,Chunmei Hou,Gaizhi Zhu,He Xiao,Ying Fang,Renxi Wang

doi:10.18632/oncotarget.19002

Abstract

Previous studies have shown that under normal physiological conditions thymic B cells play a critical function in T cell negative selection. We tested the effect of thymic B cells on thymic T-cell differentiation in autoimmune diseases including systemic lupus erythematosus (SLE). We found that thymic B cells and CD8- CD4+ and CD4-CD8+T cells increased, whereas CD4+CD8+T cells decreased in lupus-prone mice. Once B cells were reduced, the change was reversed. Furthermore, we found that B cells blocked thymic immature single positive (ISP) CD4-CD8+CD3lo/-RORγt- T cells progression into CD4+CD8+T cells. Interestingly, we found a novel population of thymic immature T cells (CD4-CD8+CD3loRORγt+) that were induced into mature CD4-CD8+CD3+RORγt+T cells by B cells in lupus-prone mice. Importantly, we found that IgG, produced by thymic B cells, played a critical role in the differentiation of thymic CD8+ISP and mature RORγt+CD8+ T cells in lupus-prone mice. In conclusion, B cells blocked the differentiation from thymic CD8+ISP and induced the differentiation of a novel immature CD4-CD8+CD3loRORγt+T cells into mature RORγt+CD8+ T cells by secreting IgG antibody in lupus-prone mice.

Highlights

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by B cell hyper-reactivity, abundant production of autoantibodies, and subsequent formation of immune complexes leading to tissue damage [1, 2]
Flow cytometry (FACS) analysis demonstrated that the percentages and the absolute numbers of thymic B cells increased in lupus-prone mice (Figure 1A1C)
We found that thymic B cells increased in mice that received B cells from non-lupus-prone and lupus-prone mice (Supplementary Figure S5A-S5C)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by B cell hyper-reactivity, abundant production of autoantibodies, and subsequent formation of immune complexes leading to tissue damage [1, 2]. The pathogenesis of SLE remains unclear, the prevalence of autoantibodies early on before clinical symptoms of SLE are found implicates B cell dysregulation as a contributing factor to disease [5, 6]. B-cell-targeting drugs such as Belimumab and Rituximab, have proven to be extremely effective in SLE patients [7,8,9] suggesting that B cell dysregulation plays a critical role in the pathogenesis of SLE. Apart from B cells, autoreactive T cells play significant roles in SLE disease pathogenesis [10]. The CD4+/CD8+ T cell ratio decreased in SLE patients [14] and there was a marked increase in the frequency and functional activity of Th17, Tc17 and other T-cell subsets in active compared to inactive SLE [15]

Methods

Results

Conclusion